Peripheral education of the immune system by colonic commensal microbiota

Abstract

SummaryThe instruction of the immune system to be tolerant of self, thereby preventing autoimmunity, is facilitated by the education of T cells in a specialized organ, the thymus, where self-reactive cells are either eliminated or differentiated into tolerogenic Foxp3+ regulatory T(Treg) cells1. However, it is unknown whether T cells are also educated to be tolerant of foreign antigens, such as those from commensal bacteria, in order to prevent immunopathology such as inflammatory bowel disease2–4. Here, we show that encounter with commensal microbiota results in the peripheral generation of Treg cells, rather than pathogenic effectors. We observed that colonic Treg cells utilized T cell antigen receptors (TCRs)different from those used by Treg cells in other locations, implying an important role for local antigens in shaping the colonic Treg cell population. Many of the local antigens appeared to be derived from commensal bacteria based on the in vitro reactivity of common colon Treg TCRs. Interestingly, these TCRs did not facilitate thymic Treg cell development, implying that manycolonic Treg cells arise instead via antigen-driven peripheral Treg cell development. Further analysis of two of these TCRs by the creation of retroviral bone marrow chimeras and a TCR transgenic linerevealed that microbiota indigenous to our mouse colony was required for the generation of colonic Treg cells from otherwise naive T cells. If T cells expressing these TCRs fail to undergo Treg cell development and instead become effector cells, they have the potential to induce colitis, as evidenced by adoptive transfer studies. These results suggest that the efficient peripheral generation of antigen-specific populations of Treg cells in response to an individual’s microbiota provides important post-thymic education of the immune system to foreign antigens, thereby providing tolerance to commensal microbiota.

The Intestine: where amazing things happen

“…However, an important piece of knowledge was still missing: are these iTreg cells generated against self or foreign antigens derived from the commensal bacteria? The study by Lathrop et al [3] answered this question, showing that iTregs are indeed induced by TCR recognition of commensal antigens. In turn they suggest the intestine as the key organ for the induction of peripheral tolerance.…”

“…Based on these results one would expect that germ-free mice, which do not have bacteria in the intestine, have reduced numbers of Treg cells in the colon. However, this was not the case [3], and one possible explanation for this controversy would be that tTreg cells compensate for the paucity of iTreg cells in the colon of germ-free mice. In line with this hypothesis, the authors found that Treg cells in the colon of germ-free mice expressed higher levels of the transcription factor Helios, which is preferentially expressed by tTreg cells [4].…”

“…First, Lathrop et al [3] found that Treg cells and effector T cells in the intestine express very different TCRs from each other, which were in turn different again from the TCRs of T cells in other organs. These data suggested that the colonic T cell population is strongly shaped by the local antigens in the intestine.…”

Foxp3+ T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation

“…1 Recent findings indicate that under homeostatic conditions, such peripherally induced Tregs (pTregs) are of functional importance mainly at feto-maternal interfaces and for maintaining tolerance to food-and microbiota-derived antigens at mucosal sites. [2][3][4][5][6] In addition to differences in ontogeny, there is growing evidence that Tregs having undergone antigen-specific stimulation may differ significantly from their naive recirculating counterparts in terms of activation status, migratory potential, and regulatory function. 7,8 Together with the notion that Tregs having different origins or anatomical locations display distinct but specific gene expression profiles, 9 this has led to the discovery of different functional Treg subpopulations, termed ''effector'' Treg lineages.…”

Microbiote intestinal et développement du système immunitaire

“…La grande sensibilité de la SFB aux mécanismes de défense de l'hôte, qu'elle contribue à induire, garantit son innocuité, sa transformation sous forme de spores lui permettant de survivre, et d'assurer sa transmission verticale [30]. Au-delà des interactions locales, le microbiote influence profondé-ment les réponses innées et adaptatives de l'hôte en périphérie [5,35] et semble ainsi capable de préparer le système immunitaire à répondre efficacement aux pathogènes. Les mécanismes de ces effets en péri-phérie sont incomplètement élucidés, mais sont principalement attribués à la diffusion vers la périphérie de facteurs solubles dérivés des bactéries et de leur métabolisme [2,36,37].…”